tbuckley/cabot-search huggingface dataset:
Rates and Factors Associated With Documentation of Diagnostic Codes for Long COVID in the National Veterans Affairs Health Care System
Authors: George N. Ioannou, Aaron Baraff, Alexandra Fox, Troy Shahoumian, Alex Hickok, Ann M. O’Hare, Amy S. B. Bohnert, Edward J. Boyko, Matthew L. Maciejewski, C. Barrett Bowling, Elizabeth Viglianti, Theodore J. Iwashyna, Denise M. Hynes
Journal: JAMA Network Open (2022)

Some persons infected with SARS-CoV-2 experience symptoms or impairments many months after acute infection.To determine the rates, clinical setting, and factors associated with documented receipt of COVID-19-related care 3 or more months after acute infection.This retrospective cohort study used data from the US Department of Veterans Affairs health care system. Participants included persons with a positive SARS-CoV-2 test between February 1, 2020, and April 30, 2021, who were still alive 3 months after infection and did not have evidence of reinfection. Data analysis was performed from February 2020 to December 2021.Positive SARS-CoV-2 test.Rates and factors associated with documentation of COVID-19-related International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes (U07.1, Z86.16, U09.9, and J12.82) 3 or more months after acute infection (hereafter, long-COVID care), with follow-up extending to December 31, 2021.Among 198 601 SARS-CoV-2-positive persons included in the study, the mean (SD) age was 60.4 (17.7) years, 176 942 individuals (89.1%) were male, 133 924 (67.4%) were White, 44 733 (22.5%) were Black, and 19 735 (9.9%) were Hispanic. During a mean (SD) follow-up of 13.5 (3.6) months, long-COVID care was documented in a wide variety of clinics, most commonly primary care and general internal medicine (18 634 of 56 310 encounters [33.1%]), pulmonary (7360 of 56 310 encounters [13.1%]), and geriatrics (5454 of 56 310 encounters [9.7%]). Long-COVID care was documented in 26 745 cohort members (13.5%), with great variability across geographical regions (range, 10.8%-18.1%) and medical centers (range, 3.0%-41.0%). Factors significantly associated with documented long-COVID care included older age, Black or American Indian/Alaska Native race, Hispanic ethnicity, geographical region, high Charlson Comorbidity Index score, having documented symptoms at the time of acute infection (adjusted odds ratio [AOR], 1.71; 95% CI, 1.65-1.78) and requiring hospitalization (AOR, 2.60; 95% CI, 2.51-2.69) or mechanical ventilation (AOR, 2.46; 95% CI, 2.26-2.69). Patients who were fully vaccinated at the time of infection were less likely to receive long-COVID care (AOR, 0.78; 95% CI, 0.68-0.90).Long-COVID care was documented in a variety of clinical settings, with great variability across regions and medical centers and was documented more commonly in older persons, those with higher comorbidity burden, those with more severe acute COVID-19 presentation and those who were unvaccinated at the time of infection. These findings provide support and guidance for health care systems to develop systematic approaches to the evaluation and management of patients who may be experiencing long COVID.
Trends in Participation in Medicare Among Psychiatrists and Psychiatric Mental Health Nurse Practitioners, 2013-2019
Authors: Seokmin Oh, Alex McDowell, Nicole M. Benson, Benjamin Lê Cook, Vicki Fung
Journal: JAMA Network Open (2022)

Medicare psychiatrists in 2013 and 2019, although increases in the proportion of HSAs with PMHNPs may have helped some rural areas maintain access to psychiatric prescribers.A limitation is that this study excluded clinical nurse specialists and psychologists who can prescribe in some states.We may have underestimated PMHNP participation in Medicare due to the prevalence of incident-to-billing under which care provided by PMHNPs is billed under a physician's National Provider Identifier number. 6Identification of care delivery models that maximize the availability of different clinician types is critical for improving access to mental health care, particularly in rural areas.
A Secondary Metabolic Enzyme Functioned as an Evolutionary Seed of a Primary Metabolic Enzyme
Authors: Jun Kawaguchi, Hikaru Mori, Noritaka Iwai, Masaaki Wachi
Journal: Molecular Biology and Evolution (2022)

Abstract The antibiotic alaremycin has a structure that resembles that of 5-aminolevulinic acid (ALA), a universal precursor of porphyrins, and inhibits porphyrin biosynthesis. Genome sequencing of the alaremycin-producing bacterial strain and enzymatic analysis revealed that the first step of alaremcyin biosynthesis is catalysed by the enzyme, AlmA, which exhibits a high degree of similarity to 5-aminolevulinate synthase (ALAS) expressed by animals, protozoa, fungi, and α-proteobacteria. Site-directed mutagenesis of AlmA revealed that the substitution of two amino acids residues around the substrate binding pocket transformed its substrate specificity from that of alaremycin precursor synthesis to ALA synthesis. To estimate the evolutionary trajectory of AlmA and ALAS, we performed an ancestral sequence reconstitution analysis based on a phylogenetic tree of AlmA and ALAS. The reconstructed common ancestral enzyme of AlmA and ALAS exhibited alaremycin precursor synthetic activity, rather than ALA synthetic activity. These results suggest that ALAS evolved from an AlmA-like enzyme. We propose a new evolutionary hypothesis in which a non-essential secondary metabolic enzyme acts as an ‘evolutionary seed’ to generate an essential primary metabolic enzyme.
Complementary Nck1/2 Signaling in Podocytes Controls α Actinin-4–Mediated Actin Organization, Adhesion, and Basement Membrane Composition
Authors: Claire E. Martin, Noah J. Phippen, Ava Keyvani Chahi, Manali Tilak, Sara L. Banerjee, Peihua Lu, Laura A. New, Casey R. Williamson, Mathew J. Platt, Jeremy A. Simpson, Mira Krendel, Nicolas Bisson, Anne-Claude Gingras, Nina Jones
Journal: Journal of the American Society of Nephrology (2022)

Significance Statement Podocyte detachment is a major contributor to kidney disease progression, yet the mechanisms controlling podocyte adhesion are not well understood. We identified novel roles for Nck1 and Nck2 cytoskeletal adaptor proteins in cell adhesion through regulation of actin bundling at focal adhesions via α actinin-4. In vivo , loss of Nck1 and/or Nck2 increases basement membrane matrix deposition and renders podocytes more susceptible to damage after injury and with aging. More severe defects are observed with Nck2 deficiency, consistent with identification of distinct effector proteins. The results suggest an essential role for Nck adaptors as molecular hubs integrating multiple actin-based signals to control podocyte adhesion dynamics. Background Maintenance of the kidney filtration barrier requires coordinated interactions between podocytes and the underlying glomerular basement membrane (GBM). GBM ligands bind podocyte integrins, which triggers actin-based signaling events critical for adhesion. Nck1/2 adaptors have emerged as essential regulators of podocyte cytoskeletal dynamics. However, the precise signaling mechanisms mediated by Nck1/2 adaptors in podocytes remain to be fully elucidated. Methods We generated podocytes deficient in Nck1 and Nck2 and used transcriptomic approaches to profile expression differences. Proteomic techniques identified specific binding partners for Nck1 and Nck2 in podocytes. We used cultured podocytes and mice deficient in Nck1 and/or Nck2, along with podocyte injury models, to comprehensively verify our findings. Results Compound loss of Nck1/2 altered expression of genes involved in actin binding, cell adhesion, and extracellular matrix composition. Accordingly, Nck1/2-deficient podocytes showed defects in actin organization and cell adhesion in vitro , with podocyte detachment and altered GBM morphology present in vivo . We identified distinct interactomes for Nck1 and Nck2 and uncovered a mechanism by which Nck1 and Nck2 cooperate to regulate actin bundling at focal adhesions via α actinin-4. Furthermore, loss of Nck1 or Nck2 resulted in increased matrix deposition in vivo , with more prominent defects in Nck2-deficient mice, consistent with enhanced susceptibility to podocyte injury. Conclusion These findings reveal distinct, yet complementary, roles for Nck proteins in regulating podocyte adhesion, controlling GBM composition, and sustaining filtration barrier integrity.
Modulation of BCL-2 in Both T Cells and Tumor Cells to Enhance Chimeric Antigen Receptor T-cell Immunotherapy against Cancer
Authors: Yong Gu Lee, Puneeth Guruprasad, Guido Ghilardi, Raymone Pajarillo, Christopher Tor Sauter, Ruchi Patel, Hatcher J. Ballard, Seok Jae Hong, Inkook Chun, Nicholas Yang, Kimberly V. Amelsberg, Katherine D. Cummins, Jakub Svoboda, Saar Gill, Elise A. Chong, Khrystyna North, Sarah E. Church, Joseph A. Fraietta, Wan-Jung Chang, Simon F. Lacey, Xueqing Maggie Lu, Yunlin Zhang, Kanupriya Whig, David C. Schultz, Sara Cherry, James Gerson, Stephen J. Schuster, Patrizia Porazzi, Marco Ruella
Journal: Cancer Discovery (2022)

Abstract Chimeric antigen receptor T-cell (CART) immunotherapy led to unprecedented responses in patients with refractory/relapsed B-cell non-Hodgkin lymphoma (NHL); nevertheless, two thirds of patients experience treatment failure. Resistance to apoptosis is a key feature of cancer cells, and it is associated with treatment failure. In 87 patients with NHL treated with anti-CD19 CART, we found that chromosomal alteration of B-cell lymphoma 2 (BCL-2), a critical antiapoptotic regulator, in lymphoma cells was associated with reduced survival. Therefore, we combined CART19 with the FDA-approved BCL-2 inhibitor venetoclax and demonstrated in vivo synergy in venetoclax-sensitive NHL. However, higher venetoclax doses needed for venetoclax-resistant lymphomas resulted in CART toxicity. To overcome this limitation, we developed venetoclax-resistant CART by overexpressing mutated BCL-2(F104L), which is not recognized by venetoclax. Notably, BCL-2(F104L)-CART19 synergized with venetoclax in multiple lymphoma xenograft models. Furthermore, we uncovered that BCL-2 overexpression in T cells intrinsically enhanced CART antitumor activity in preclinical models and in patients by prolonging CART persistence. Significance: This study highlights the role of BCL-2 in resistance to CART immunotherapy for cancer and introduces a novel concept for combination therapies—the engineering of CART cells to make them resistant to proapoptotic small molecules, thereby enhancing the therapeutic index of these combination therapies. This article is highlighted in the In This Issue feature, p. 2221
Epithelial HVEM maintains intraepithelial T cell survival and contributes to host protection
Authors: Goo-Young Seo, Daisuke Takahashi, Qingyang Wang, Zbigniew Mikulski, Angeline Chen, Ting-Fang Chou, Paola Marcovecchio, Sara McArdle, Ashu Sethi, Jr-Wen Shui, Masumi Takahashi, Charles D. Surh, Hilde Cheroutre, Mitchell Kronenberg
Journal: Science Immunology (2022)

Intraepithelial T cells (IETs) are in close contact with intestinal epithelial cells and the underlying basement membrane, and they detect invasive pathogens. How intestinal epithelial cells and basement membrane influence IET survival and function, at steady state or after infection, is unclear. The herpes virus entry mediator (HVEM), a member of the TNF receptor superfamily, is constitutively expressed by intestinal epithelial cells and is important for protection from pathogenic bacteria. Here, we showed that at steady-state LIGHT, an HVEM ligand, binding to epithelial HVEM promoted the survival of small intestine IETs. RNA-seq and addition of HVEM ligands to epithelial organoids indicated that HVEM increased epithelial synthesis of basement membrane proteins, including collagen IV, which bound to β 1 integrins expressed by IETs. Therefore, we proposed that IET survival depended on β 1 integrin binding to collagen IV and showed that β 1 integrin–collagen IV interactions supported IET survival in vitro. Moreover, the absence of β 1 integrin expression by T lymphocytes decreased TCR αβ + IETs in vivo. Intravital microscopy showed that the patrolling movement of IETs was reduced without epithelial HVEM. As likely consequences of decreased number and movement, protective responses to Salmonella enterica were reduced in mice lacking either epithelial HVEM, HVEM ligands, or β 1 integrins. Therefore, IETs, at steady state and after infection, depended on HVEM expressed by epithelial cells for the synthesis of collagen IV by epithelial cells. Collagen IV engaged β 1 integrins on IETs that were important for their maintenance and for their protective function in mucosal immunity.
Cross-species transcriptome analysis for early detection and specific therapeutic targeting of human lupus nephritis
Authors: Eleni Frangou, Panagiotis Garantziotis, Maria Grigoriou, Aggelos Banos, Dionysis Nikolopoulos, Antigone Pieta, Stavros A Doumas, Antonis Fanouriakis, Aikaterini Hatzioannou, Theodora Manolakou, Themis Alissafi, Panayotis Verginis, Emmanouil Athanasiadis, Emmanouil Dermitzakis, George Bertsias, Anastasia Filia, Dimitrios T Boumpas
Journal: Annals of the Rheumatic Diseases (2022)

Patients with lupus nephritis (LN) are in urgent need for early diagnosis and therapeutic interventions targeting aberrant molecular pathways enriched in affected kidneys.We used mRNA-sequencing in effector (spleen) and target (kidneys, brain) tissues from lupus and control mice at sequential time points, and in the blood from 367 individuals (261 systemic lupus erythematosus (SLE) patients and 106 healthy individuals). Comparative cross-tissue and cross-species analyses were performed. The human dataset was split into training and validation sets and machine learning was applied to build LN predictive models.In murine SLE, we defined a kidney-specific molecular signature, as well as a molecular signature that underlies transition from preclinical to overt disease and encompasses pathways linked to metabolism, innate immune system and neutrophil degranulation. The murine kidney transcriptome partially mirrors the blood transcriptome of patients with LN with 11 key transcription factors regulating the cross-species active LN molecular signature. Integrated protein-to-protein interaction and drug prediction analyses identified the kinases TRRAP, AKT2, CDK16 and SCYL1 as putative targets of these factors and capable of reversing the LN signature. Using murine kidney-specific genes as disease predictors and machine-learning training of the human RNA-sequencing dataset, we developed and validated a peripheral blood-based algorithm that discriminates LN patients from normal individuals (based on 18 genes) and non-LN SLE patients (based on 20 genes) with excellent sensitivity and specificity (area under the curve range from 0.80 to 0.99).Machine-learning analysis of a large whole blood RNA-sequencing dataset of SLE patients using human orthologs of mouse kidney-specific genes can be used for early, non-invasive diagnosis and therapeutic targeting of LN. The kidney-specific gene predictors may facilitate prevention and early intervention trials.
Boosting Antitumor Immunity with an Expanded Neoepitope Landscape
Authors: Remco Nagel, Abhijeet Pataskar, Julien Champagne, Reuven Agami
Journal: Cancer Research (2022)

Abstract Immune-checkpoint blockade therapy has been successfully applied to many cancers, particularly tumors that harbor a high mutational burden and consequently express a high abundance of neoantigens. However, novel approaches are needed to improve the efficacy of immunotherapy for treating tumors that lack a high load of classic genetically derived neoantigens. Recent discoveries of broad classes of nongenetically encoded and inducible neoepitopes open up new avenues for therapeutic development to enhance sensitivity to immunotherapies. In this review, we discuss recent work on neoantigen discovery, with an emphasis on novel classes of noncanonical neoepitopes.
<i>Helicobacter pylori</i> actively suppresses innate immune nucleic acid receptors
Authors: Samuel D.R. Dooyema, Jennifer M. Noto, Lydia E. Wroblewski, M. Blanca Piazuelo, Uma Krishna, Giovanni Suarez, Judith Romero-Gallo, Alberto G. Delgado, Richard M. Peek
Journal: Gut Microbes (2022)

Chronic mucosal pathogens have evolved multiple strategies to manipulate the host immune response; consequently, microbes contribute to the development of >2 million cases of cancer/year. Gastric adenocarcinoma is the fourth leading cause of cancer-related death and Helicobacter pylori confers the highest risk for this disease. Gastric innate immune effectors can either eliminate bacteria or mobilize adaptive immune responses including Toll-like receptors (TLRs), and cytosolic DNA sensor/adaptor proteins (e.g., stimulator of interferon genes, STING). The H. pylori strain-specific cag type IV secretion system (T4SS) augments gastric cancer risk and translocates DNA into epithelial cells where it activates the microbial DNA sensor TLR9 and suppresses injury in vivo; however, the ability of H. pylori to suppress additional nucleic acid PRRs within the context of chronic gastric inflammation and injury remains undefined. In this study, in vitro and ex vivo experiments identified a novel mechanism through which H. pylori actively suppresses STING and RIG-I signaling via downregulation of IRF3 activation. In vivo, the use of genetically deficient mice revealed that Th17 inflammatory responses are heightened following H. pylori infection within the context of Sting deficiency in conjunction with increased expression of a known host immune regulator, Trim30a. This novel mechanism of immune suppression by H. pylori is likely a critical component of a finely tuned rheostat that not only regulates the initial innate immune response, but also drives chronic gastric inflammation and injury.
Britain’s not working
Authors: Martin McKee, Lucinda Hiam
Journal: BMJ (2022)

Aims: To determine whether abused and non-abused children differ in the extent and pattern of bruising, and whether any differences which exist are sufficiently great to develop a score to assist in the diagnosis of abuse. Methods: Total length of bruising in 12 areas of the body was determined in 133 physically abused and 189 control children aged 1–14 years. Results: Our method of recording bruises by site, maximum dimension, and shape was easy to use. There were clear differences between cases and controls in the total length of bruises. These differences were at their greatest in the head and neck and were less notable in the limbs. A scoring system was developed using logistic regression analysis using total lengths of bruising in five regions of the body. Good discrimination between the two sets of children was achieved using this score; by including a variable that indicates whether a bruise had a recognisable shape the discrimination could be made even better. Given a prior probability of abuse the score can be used to give posterior odds of abuse, given a particular bruising pattern. Conclusions: The scoring system provides a measure that discriminates between abused and non-abused children, which should be straightforward to implement, though the results must be interpreted carefully. We do not see this score as replacing the complex qualitative analysis of the diagnosis of abuse. This clearly includes history as well as examination, but rather as the beginning of the development of an important aid in this process.
What poo tells us: wastewater surveillance comes of age amid covid, monkeypox, and polio
Authors: Bryn Nelson
Journal: BMJ (2022)

<h3>Abstract</h3> The well-documented, species-rich, and diverse group of ants (Formicidae) are important ecological bioindicators for species richness, ecosystem health, and biodiversity, but ant species identification is complex and requires specific knowledge. In the past few years, insect identification from images has seen increasing interest and success, with processing speed improving and costs lowering. Here we propose deep learning (in the form of a convolutional neural network (CNN)) to classify ants at species level using AntWeb images. We used an Inception-ResNet-V2-based CNN to classify ant images, and three shot types with 10,204 images for 97 species, in addition to a multi-view approach, for training and testing the CNN while also testing a worker-only set and an AntWeb protocol-deviant test set. Top 1 accuracy reached 62% - 81%, top 3 accuracy 80% - 92%, and genus accuracy 79% - 95% on species classification for different shot type approaches. The head shot type outperformed other shot type approaches. Genus accuracy was broadly similar to top 3 accuracy. Removing reproductives from the test data improved accuracy only slightly. Accuracy on AntWeb protocol-deviant data was very low. In addition, we make recommendations for future work concerning image threshold, distribution, and quality, multi-view approaches, metadata, and on protocols; potentially leading to higher accuracy with less computational effort.
Gut bacteria interact directly with colonic mast cells in a humanized mouse model of IBS
Authors: Chiko Shimbori, Giada De Palma, Lauren Baerg, Jun Lu, Elena F. Verdu, David E. Reed, Stephen Vanner, Stephen M. Collins, Premysl Bercik
Journal: Gut Microbes (2022)

Both mast cells and microbiota play important roles in the pathogenesis of Irritable Bowel Syndrome (IBS), however the precise mechanisms are unknown. Using microbiota-humanized IBS mouse model, we show that colonic mast cells and mast cells co-localized with neurons were higher in mice colonized with IBS microbiota compared with those with healthy control (HC) microbiota. In situ hybridization showed presence of IBS, but not control microbiota, in the lamina propria and RNAscope demonstrated frequent co-localization of IBS bacteria and mast cells. TLR4 and H4 receptor expression was higher in mice with IBS microbiota, and in peritoneal-derived and bone marrow-derived mast cells (BMMCs) stimulated with IBS bacterial supernatant, which also increased BMMCs degranulation, chemotaxis, adherence and histamine release. While both TLR4 and H4 receptor inhibitors prevented BMMCs degranulation, only the latter attenuated their chemotaxis. We provide novel insights into the mechanisms, which contribute to gut dysfunction and visceral hypersensitivity in IBS.
Supporting the Public Health Workforce Requires Collective Actions to Address Harassment and Threats
Authors: Sarah E. Gollust
Journal: JAMA Network Open (2022)

Rachel J. Topazian, BA; Emma E. McGinty, PhD, MS; Hahrie Han, PhD; Adam S. Levine, PhD; Kelly E. Anderson, PhD, MPP; Rachel Presskreischer, PhD, MS; Colleen L. Barry, PhD, MPP